Conditions have been developed for: (a) in vitro stimulation of influenza virus-immune cytotoxic effector cells in human peripheral blood leukocyte (PBL) populations; and (b) measurement of effector cell activity on virus-infected cryopreserved human PBL target cells. Effector cells generated in vitro are influenza type (but not subtype) specific and are HLA-A and HLA-B restricted. The cytotoxic response appears to be controlled by HLA-linked immune response (Ir) genes since: (a) cytotoxic activity is predominantly associated with antigens of only one haplotype; and (b) effector cells from certain donors recognize virus in association with some but not all self HLA-A and -B antigens. This Ir gene control is HLA-linked and antigen-specific, since preferential recognition among HLA-identical siblings is different for influenza A and B viruses.